[3, 2-d] triazoles of the pregnane series



United States Patent 3,281,414 [3,2-d1TRIAZOLES OF THE PREGNANE SERIESJohn Fried, Plainfield, and Helmut Mrozik, Matawan, N.J., assignorstoMerck & Co., Inc., Rahway, N.J., a corporation of New Jersey No Drawing.Filed June 17, 1963, Ser. No. 288,431 18 Claims. (Cl. 260239.5)

This invention relates to novel steroids and to processes of making thesame. More particularly, this invention relates to novel[3,2-d1triazoles of the pregnane series. These novel steroids arerepresented by the following structural formula:

The steroid nucleus may have attached thereto substituents such ashydrogen, methyl or halogen at 0-6; hydrogen or a-halogen at C-9;hydrogen, keto or fi-hydroxy at C-11; i -halogen at C-11 when a-halogenis also present at C9; hydrogen, a-hydroxy, OL-flllOl'O, methyl ormethylene at C-16; the 16a,17a-acetals or ketals of16a,17a-dihydroxygroups when hydrogen, hydroxy, chloro or fluoro ispresent at C21; and hydrogen, hydroxy, chloro, fiuoro, acyloxy or thephosphate esters at C-21. The substituent present at one of the threenitrogens of the triazole ring (positions 1', 2 or 3) may be hydrogen,acy-l, alkyl, cycloalkyl, aryl, a-ralkyl, a heterocyclic nucleus, orsubstituted derivatives thereof. A double bond may be present at the 4-5position, the 6-7 position, or both positions.

The above described [3,2-d]triazoles of the pregnane series produced inaccordance with the present invention possess high anti-inflammatoryactivity, and are especially efieetive for the treatment of arthritisand related diseases since they can be administered for theircortisonelike action in low dosage thereby minimizing undesirable sideeffects.

The 2-substituted-4-pregneno (or 4,6-pregnadieno)[3,2-d]-2H-1',2',3'-triazoles of the pregnane series which have thefollowing formula, or which are the A -analogues of compounds having thefollowing structure, are prepared according to the procedures outlinedin Flow Sheet A.

Its-N ice drogen, a-fluoro, a-methyl, fi-methyl and methylene; R is amember of the group consisting of hydrogen, acyloxy, chloro and fiuoro;R is a member of the group consisting of hydrogen, alkyl, aralkyl,cycloalkyl, aryl, a heterocyclic nucleus, and substituted derivativesthereof; and X is a member of the group consisting of hydrogen andhalogen.

The 17 x,21-dihydroxy-4-pregnene- (or 4,6-pregnadiene)-3,20-dione usedas starting material (Flow Sheet A, Compound 1) is protected at the 17,20 and 21 positions by suitable protecting groups. In a preferredembodiment of our invention these positions of the steroid molecule areprotected by forming the 17a,20,20,21-bis(methylenedioxy)2-derivative(Compound 2). Thus, Compound 1 of Flow Sheet A, and the A -analoguesthere-of, react with aqueous formaldehyde solutions in the presence ofstrong acid to form the corresponding 17a,20,20,21bis(methylenedioxy)-steroids. For example, cold con centrated H01 andformalin are added to a stirred suspension of the steroid in chloroform,cooled to about 0 C. The mixture is then allowed to come to roomtemperature and stirred for several hours to afford the corresponding17a,20,20,21 bis(methylenediox'y) derivative (Compound 2).

The above named starting materials for our invention can be prepared bythe introduction of the various substituents, namely the 16a-methyl-,16,6methyl-, l6-methylene-, 6a-methyl-, 6a-fluoroor the 9a-fluoro-groupsinto a 17a,21-dihydroxy-4-pregnene-3,ZO-dione according to knownprocedures capable of general application. More than one substituent maybe introduced into the unsubstituted steroid in any order, although itis generally preferred to introduce a 9ot-halogen substituent last.

Procedures for the introduction of the following groups into certain[3,2-d]triazoles of the pregnane series are disclosed in these examples:6a-methyl-A in Examples 8, 14; 6p-methyl-A in Examples 8, 14; 6-methyl-Ain Examples 5, 11; 9a-fluoro in Examples 9 and 23; 6ozhalogen inExamples 7, 10, 15; 6t3-hallogen in Examples 6, 16; ll-desoxy in Example13.

These procedures may be adapted by those skilled in the art to thesimilar 4-pregnene and 4,6-pregnadiene compounds used as startingmaterials.

The starting materials for the various lfioc-fillOI'O-COITI- pounds areprepared by the methods described in EX- ample 21.

An 11B,17a,21-trihydroxy-4-pregnene-3,ZO-dione compound may be convertedinto the correspondingly substituted901,1l;3-dichloro-17a,21-dihydroxy-4-pregnene 3, 20-dione compound byfirst dehydrating the 11fi,17a,21- trihydroxy 4-pregnene-3,20-dione atthe 9(11)-position to form the corresponding 9(l1)-1pregnene, thenacetylating at the 21-position, and finally halogenating at the c,llfl-positions, for example, following the detailed procedures given inExample 12. This procedure is likewise applicable to the A -analogues.

In a preferred embodiment of our invention, the 11- ket-o-steroids arepreferably prepared by oxidation of the correspondingllp-hydroxy-ster-oid, for example, with chromium trioxide in anon-aqueous base such as pyridine. If desired, however, the 17a,20,20,21bis(methylenedioxy)-4-pregnene- (or 4,6-pregnadiene)-3,1l-dione may beprepared directly by the reaction of the 17a,21-dihydroxy- 4-pregnene-(or 4,6-pregnadiene)-3,11,20-trione with formaldehyde solution in thepresence of an acid as described in the first step of Example 1.

Upon treatment of the 17u,20,20,2l-bis(methylenedioxy)-4-pregnene- (or4,6-pregnadiene)-3-one compound with an alkyl formate and sodium hydridein an inert atmosphere there is formed the corresponding 1711,2030, 2l-bis methylenedioxy) -2-hydroxymethylene-4-pregnene- (or4,6-pregnadiene)-3-one (Compound 3). For example, the steroid isdissolvedin a solvent such as benzene and the resulting solution iscooled to room temperature and treated with ethyl formate. The air inthe system is replaced with nitrogen, sodium hydride is added and themixture is stirred at room temperature for several hours.

The 2-hydroxymethylene-compound is reacted with nitrous acid to form thecorresponding 17a,20,20,21-bis (rmethylenedioxy)-4-pregnene (or4,6-pregnadiene)-3-one (Compound 4). In a preferred embodiment of ourinvention the steroid is dissolved in a solution of glacial acetic acidin a solvent such as methylene chloride. The solution is then cooled toabout C. An aqueous solution of sodium nitrite is then added to thecooled solution with stirring in an inert atmosphere. The reactionmixture is allowed to stirat 0 C. for about 30 minutes to .form the2-hydroxyimino-steriod (Compound 4).-

The 2-hydroxyimino-steroid is reacted with hydrazine,

for example, by refluxing in an inert atmosphere for several hours, toform the 17u,20,20,21bis(methy1enedioxy)-4-pregneno- (or4,6-pregnadieno)-[3,2-d]triazole (Compound 6 where R is hydrogen).

The 2-hydroxyimino-steroid is reacted with a monosubstituted hydrazineto form the corresponding 1704,20, 20,21 bis(methylenedioxy) 2hydroxyimino 3 (substituted)-hydrazono-4-pregnene- (or4,6-pregnadiene)-3- one (Compound 5). This reaction takes place, forexample, on allowing a solution of the steroid and the sub-.

stituted hydrazine to stand for several hours at room temperature.

Upon treatment of the 2-hydroxyimino-3-(substituted)- hydrazono-steroid(Compound 5) with a dehydrating agent such as phosphorus pentachloridethe corresponding l7rx,20,20,2l-bis(methylenedioxy)-2-substituted-4pregneno- (or 4,6-pregnadieno)-[3,2-d]-2'H-1',2',3'-triazole is formed(Compound 6 where R is a radical other than hydrogen).

Alternately, the 2-hydroxyimino-steroid (Compound 4) is converteddirectly into the corresponding 2'-substituted- 4-pregneno- (or4,6-pregnadieno)-[3,2-d]-2H-1,2',3-triazole (Compound 6) by reactionwith a monosubstituted hydrazine under suitable operating conditions.

Among the monosubstituted hydrazines which may be used for the processof our invention are: alkylhydrazines, such as methylhydrazine,ethylhydrazine, propylhydrazines, butylhydrazines,fl-hydroxyethylhydrazine, cycloalkylhydrazines; arylhydrazines which maybe derived from any aromatic nucleus including phenylhydrazine and.

the substituted phenylhydrazines, such as 0-, m-, andphalophenylhydrazines, o-, m-, and p-tolyhydrazine, o-, rn-, andp-alkoxyphenylhydrazines, o-, -m-, and p-nitrophenylhydrazines,l-hydrazinonaphthalene, Z-hydrazinopyridine, B-hydrazinopyridine,4-hydrazinopyridine, 4-hydrazinopyridine, oxide, and2-hydrazinopyrimidine, 2-hydrazinothiophene, 3-hydrazinothiophene;aralkylhydrazines, such as benzylhydrazine and phenylethylenehydrazine.

There are thus produced the corresponding 2'-substituted-4-pregneno- (or4,6-pregnadieno)-[3,2-dl-2H-1, 2,3-triazoles including: 2'-alkyl such as2'-methyl-, 2'- ethyl-, 2-butyl-, 2'-propyl-, 2'-(B-hydroxyethyl)-;2'-cycloalkyl-; 2'-arylwhich may be derived from any aromatic nucleus,including 2-phenyland the 2-substituted-phenyl derivatives such as o-,m-, and p-halophenyl; o-, m-, and

I aralky1-, such as 2-benzyland 2'phenyethenyl-4-preg-- of the1'-alkyl-4-pregneno- (or 4,6-pregnadieno)-[3,2-d]- neno- (or4,6-pregnadieno)-[3,2-d]-3H-1',2',3'-triazole (see Flow Sheet B). Themixture is separated by chromatography. In a preferred embodiment of ourinvention alkylation is carried out by treating a solution of thesteroid with sodium hydride and an alkyl iodide. 4

The 1'- and 3-substituted-4-pregneno- (or 4,6-pregnadieno)-[3,2-d]-1'H(and 3H)-1,2',3-triazoles are prepared starting with the proceduresoutlined in Flow Sheet C.

The :,21-dihydroxy-4-pregnene- (or 4,6-pregnadiene)-3,20-dione (Compound8) used as starting material is protected at the 17,20 and 21 positionsby suitable protecting groups. In a preferred embodiment of ourinvention these positions of the steroid molecule are protected byforming the 17a,20,20,21-bis(methylenedioxy)- derivative (Compound 9).Thus the 17a,21-dihydroxy-4- pregnene- (or 4,6-pregnadiene)-3,20-dione(Compound -8) is treated 'with an aqueous formaldehyde solution in thepresence of a strong acid to form the corresponding 17a,20,20,21bis(methylenedioxy) steroid (Compound 9). The latter compound isconverted to the 3-dioxolane (Compound 10) by reacting with ethyleneglycol in the presence of a strong acid. The 3-dioxolane is oxidized,for example with perbenzoic acid to form the corresponding5a-6a-epoxy-3ethylenedioxy-M-pregnane (Compound 11), which is treatedwith formic acid at room temperature to aifordthe corresponding5a-pregnano-3, 6-dione (Compound 12). The latter compound is reactedwithmorpholine to form the 3-morpholino-5u,2- pregnene-6-one (Compound 13)which on reaction with a triazolhydrocar-bon forms a mixture of the 1and 3'- substituted-6-keto-5a-pregnano-[3,2-d1-1H (and SH)-1,2',3-triazoles (Compounds 14A and 14B). The mixture is'separated bychromatography.

The triazohydrocarbons for use in the above reaction are prepared fromthe known monosubstituted hydrazines, including those listed in column3, following the procedure of Example 20. The 1- and 3-substituted-11/3-hydroxy-4-pregneno-[3,2-d] 1,2,3-triazoles which are unsubstitutedin the 6-position (Compound 18 of Flow Sheet D) are prepared accordingto the procedures of Example 4.

' Flow Sheet H) are prepared according to the procedures of Example 8.

The 1- and 3'-substituted-11fl-hydroxy-6-methyl-4,6-pregnadieno-[3,2,-d]-1,2,3-triazo'l es (Compound 23 of Flow Sheet E) areprepared accordingto the procedures of Example 5.

The 1'- and 3'-substituted-6ahalo-11B-hydroxy-4-pregnen-o-[3;2-d]-1',2,3-triazoles (Compound 32 ofFlow Sheet G) are prepared according to the procedures of Example 7.

The 1'- and3-substituted-6p-halo-11B-hydroxy-4-pregneno-[3,2-d]-1',2',3-triazoles(Compound 28 of Flow Sheet F) are prepared according to the proceduresof Example 6. I

The 1- and 3-substitute.d-6-halo-11B-hydroxy-4,6-pregnadieno-[3,2-d]-1',2,3'-triazoles (Compound 28 of Flow Sheet F) areprepared according tothe procedures of Example 6.

The various 1- and 3'-substitut'ed-9a-fiuoro-1IB-hydroXy-4-pregneno-(and4,6-pregnadieno)-[3,2-d]-1',2,3'- triazoles are prepared according tothe procedures of Flow Sheets I, J, F, G and H, detailed procedures forwhich are given in Examples 9, 11, 6, 1 0 and 8 respectively. r

' The 1'- and 3'-substituted-9d,l1fi-dichloro-4-pregneno- (and'4,6-pregnadieno)-[3,2-d]-1,2,3'-triazoles are prepared according to theprocedures of Flow Sheets K, M, N, O, P and S, detailed procedures forwhich are given in Examples 12, 14, 15, 16 and 23 respectively.

The 1- and 3'-substituted-11-desoxy-4-pregneno- (and4,6-pregnadieno)-[3,2-d]-1',2,3-triazoles are prepared according to theprocedures of Flow Sheets L, M, N, O, P and R, detailed procedures forwhich are given in Examples 13, 14, 15, 16 and 22 respectively.

Upon treatment of any of the l7o1,20,20,2l-bis(methy lenedioxy)-[3,2-d]triazole products set forth in detail above with a dilute organic acid,for example a 60% aqueous solution of formic acid, the 1711,2O,2(),21-bis (methylenedioxy)-protecting group is removed and there areobtained the corresponding 17u,21-dihydroxy-20-oxo- [3,2-d]-triazoleswhich are represented by Compounds 79A, 79B and 79C of Flow Sheet Q;

The compounds of our invention include the following:

and the (p-fluorophenyl)-derivatives thereof); likewise the M'-analogues of .all of the aforesaid compounds.

Any acyl groups present at the 2l-position and/or on -a triazolenitrogen may be removed by treating the steroid with sodium methoxide inmethanol at room temperature to form the corresponding,21-dihydroxy-20-oxo-4- pregneno- (or 4,6-pregnadieno)-[3,2-d]triazole.

The N-acyl-Zl-acylate derivatives of the above described17u,2l-dihydroxy-ZO-oxo-4-pregneno-(or 4,6-preg-'nadieno)-[3,2-d]triazoles in which both acyl groups are the same(Compound 82 of Flow Sheet Q) may be prepared by reacting a17a,21-dihydroxy-ZO-oxo-4-pregneno- (or 4,6-pregnadieno)-[3,2-d]triazolein which R is hydrogen with two equivalents of an acylating agent.

The 21-acyl derivatives of the above described triazoles in which R is H(Compound 82 of Flow Sheet Q) may be'prepared by heating anN-acyl-'l7a,2l-dihydroxy-ZO- oxo-fl-pregneno- (or4,6-p1'egnadieno)-[3,2-d]triazole 21- 'acylate with aqueous acetic acid,whereupon the N-acyl glutaric anhyride, 'succinic anhydride and thelike, in the presence of an. organic base such as pyridine.

The l7a,2l"- dihydroxy-ZO-oxo-4-pregneno- (or 4,6-pregnadieno)-[3,2-d]triazole is reacted with methane sulfonylchlor'ide'in a non-aqueous base to form the 21- mesylate (Compound .80).A steroid in which R is hydrogen is -first converted to the N-carbamylderivative before undergoing this reaction.

The 21-mes'ylate is heated with an alkali iodide to form the21-iodo-cornpound (Compound 81). In a preferred method for carrying outthis reaction, sodium iodide is added to thesteroid dissolved in acetoneand the resulting mixture is heated at-reflux temperature forapproximately one hour.

The 21-iodo-20-oXo-4-pregneno- (or 4,6-pregnadieno)- [3,2-d]-triazole isheated with an alkali bisulfite in a solvent to form the corresponding2l-desoxy-compound (Compound 84). A preferred method is to add sodiumbisulfite to a suspension of the steroid in aqueous ethanol and thenheat thejmi xture under reflux for a period of about an hour. Anycarbamyl group present at R may be removed by treating the steroid inglacial acetic acid with sodium nitrite, j

Thus the novel compounds of our invention which are formed from theabove reaction include the 2l-desoxy derivatives of all of the compoundslisted in columns 5 to 8.

The 2l-fluoro;17a-hydroxy-20-oxo-4-pregneno (and4,6-pregnadieno)-[3,2-d]triazoles (Compound 83' of Flow Sheet Q) areprepared from the corresponding 2l-mesylate by heating with an alkalifluoride in a solvent to form a mixture of a 17a,2 1-epoxy-compound andthe corresponding 2l-fluoro compound. These compounds are separated bypartition chromatography, or by chromatography on a weak adsorbent suchas silica gel. There are thus obtained the 21-fiuoro-analogues of all ofthe 21- hydroxy compounds named in columns 5 to 8.

The 2I-chloro-17u-hydroXy-20-oXo-4-pregneno (and4,6-pregnadieno)-[3,2-d]triazoles (Compound 83 of Flow Sheet Q) areprepared from the corresponding 2l-mesylate by heating with lithiumchloride, conveniently in a solvent such as dimethylformamide for aboutone hour. There are thus obtained the 21-chloro-analogues of all of the21-hydroXy-compounds named in columns 5 to 8.

The 2l-hydroxy-, 2ldesoxy-, 2l-fluoro-, and 21-chlorosteroids, wherein His present at the l6-position, are converted into the16a,l7a-dihydroxy-steroids (Compounds 93 of Flow Sheet Q) by followingthe procedures of Example 24.

The 16a,17a-dihydroxy-steroids are converted into the corresponding16a,17a-acetals or ketals (Compound 94 of Flow Sheet Q) by treating witha carbonyl reactant of the general formula:

wherein P and Q are each selected from the group consisting of hydrogen,alkyl, and aryl, and together with the carbon to which they are joined,P and Q are cycloalkyl. For example, a suspension of the free16u,17a-diol in a ketone or aldehyde is treated with a trace ofperchl-oric acid and stirred at room temperature until solution iscomplete. The ketones and aldehydes which are suitable for this purposeinclude acetaldehyde, methyl ethyl ketone, cyclohexanone, andacetophenone. In a preferred embodiment of our invention acetone isused.

The ZI-dihydrogen phosphate esters (Compound 85 of Flow Sheet Q) of allof the 21-hydroxy-compound-s listed in columns to 8, are prepared by thereaction of the corresponding 21-iodo compound (Compound 81 of FlowSheet Q) with a mixture of silver phosphate and phosphoric acid. Boththe monoand dialkali metal salts may be obtained by neutralization ofthe dihydrogen phosphate ester with an alkali methoxide. Treatment withadditional amounts of alkali methoxide will convert an N-acyl-steroid (Racyl) into the free amine (R =H)dia1kali metal salt from which thedihydrogen phosphate can be obtained by contacting with an ion exchangeresin.

All of the 4-pregneno-(and 4,6-pregnadieno)-[3,24]- triazoles describedin the foregoing structures form salts such as the hydrochloride,sulfate, chlorate, perchlorate, picrate and trichloracetate, ontreatment with the corresponding acid. Formation of crystalline salts,especially the hydrochloric salts, provides a means of isolating thetriazole.

A further embodiment of our invent-ion comprises novel pharmaceuticalcompositions containing the novel 4- pregneno-(and4,6-pregnadieno)-[3,2-d1triazoles exemplified in the foregoingstructures.

The following examples illustrate methods of carrying out the presentinvention but it is to be understood that these examples are given forpurposes of illustration and not of limitation. Details of the abovedescribed reactions are to be found in the examples.

FLOW SHEET A CHzOH wherein R is a member of the group consisting ofhydrogen, -hydroxy-, llfi-chloroand keto, but chloro is present at Ronly when X is chloro, and hydrogen is present at R only when X ishydrogen; R is a member of the group consisting of hydrogen, oc-ChlOIO-,a-fluoro-, u-methyland R is a member of the group consisting ofhydrogen-, a-fluoro-, a-methyl-, fi-rne-thyland methylene-; R is amember of the group consisting of hydrogen-, alkyl-, aralkyl-,cycloalkyl-, aryl, a heterocyclic nucleus, and substituted derivativesthereof; and X is a member of the group consisting of hydrogen andhalogen. This How Sheet also includes the M -analogues of the compoundsshown.

1 1 12 FLOW SHEET B o CE: I

l CHg R1 NW s 1 4 .1 N X N 7B R2 I ll wherein R is a member of the groupconsisting of hydrogen-, 11B-hydroxy-, llfi-chloroand keto-, but chlorois present at R only when X is chloro-, and hydrogen is present at Ronly when X is hydrogen; R is a. member of the grfpup consisting ofhydrogen-, oc-ChlOI'0-, a-fiuoroand a-methyL, R is a member of the groupconsisting of hydrogeri-, a-fiuoro-, a-methyl-, B-methyland methylene; Ris alkyl; and X is a member of the group consisting of hydrogen andhalogen. The Flow Sheet also includes the M' -analogues of thecompou-ndsshown.

FLOW SHEET C 40 wherein R is a member of the group consisting ofhydrogen-, afiUOI0-, a-methyl-, fi-mcthyland methylene; and R is amember of the group consisting of hydrogen-, alkyl-, aralkyl-,cycloalkyl-, aryl-, a heterocyclic nucleus-, and substituted derivativesthereof.

FLOW SHEET E wherein R is a member of the group consisting of hydrogen-,a-fiuoro-, a-methyb, fi-methyland methylene; R is a member of the groupconsisting of hydrogen-, acyloXy-, chloroand fluoroand R is a member ofthe group consisting of hydrogen-, alkyl-, ara1ky1-, cycloalkyl-, aryl,a heterocyclic nucleus, and substituted derivatives thereof. The brokenring designated as T is the triazole ring, the structure of the triazolering in the A compounds being the same as that of compound 14A, and thestructure of the triazole ring in the B compounds being the same as thatof compound 14B of Flow Sheet C.

FLOW SHEET F wherein R is a member of the group consisting of hydrogen-,a-fluoro-, a-methyl-, fi-methyland methylene-; R is a member of thegroup Consisting of hydrogen-,

alkyl-, aralkyl-, cycloalkyl-, aryl-, a heterocyclic nucleus-,

.and substituted derivatives thereof; X is a member of the groupconsisting of hydrogen and halogen, and X is a member of the groupconsisting of chloro and fiuoro. The broken ring designated as T is thetriazole ring, the structure of the triazole ring in the A compoundsbeing the same as that of compound 14A, and the structure of thetriazole ring in the B compounds being the same as that of compound 14Bof Flow Sheet C.

FLOW SHEET G ,OHn

wherein R is a member of the group consisting of hydrogen, a-fiuoro-,u-methy1-, fi-methyland methylene; R is a member of the group consistingof hydrogen-, alkyl-, aralkyl-, cycloalky1-, aryl-, a heterocyclicnucleus-, and substituted derivatives thereof; X is a member of thegroup consisting of hydrogen and halogen, and X is a member of the groupconsisting of chloro and fluoro. The broken ring designated as T is thetriazole ring, the structure of the triazole ring in the A compoundsbeing the same as that of compound 14A, and the structure of thetriazole ring in the B compounds being the same as that of compound 14Bof Flow Sheet C.

FLOW SHEET H wherein R is a member of the group consisting of hydrogen-,a-fluoro-, a-methy1-, fi-methyland methylene; R is a member of thegroup'consisting of hydrogen, alkyl-, aralkyl-, cycloalkyl-, aryl-, aheterocyclic nucleus, and substituted derivatives thereof; and X is amemberof the group consisting of hydrogenand halogen-. The broken 17ring designated as T is the triazole ring, the structure of the triazolering in the A compounds being the same as that of compound 14A, and thestructure of the triazole ring in the B compounds being the same as thatof compound 14B of Flow Sheet C.

FLOW SHEET I wherein R is selected from the group consisting ofhydrogen-, oc-flllOl'O, a-methyl, fi-methyl and methylene, and R 75 is amember of the group consisting of hydrogen-, alkyl-, aralkyl-,cycloalky1-, -aryl-, a heterocyclic nucleus-, and substitutedderivatives thereof. The broken ring designated as T is the triazolering, the structure of the triazole ring in the A compounds being thesame as that of compound 14A, and the structure of the triazole ring inthe B compounds being the same as that of compound 14B of Flow Sheet C.

wherein R is a member of the group consisting of hydrogen-, m-fluoro,a-meLhyl-, B-methyland methyleneand R is a member of the groupconsisting of hydrogen-, alkyl-, aralkyl-, cycloalky1-, ary1-, aheterocyclic nucleus,

FLOW SHEET K wherein R is a member of the group consisting of hydrogen-,a-fluoro-, a-methyb, B-methyland methylene-, and R is a member of thegroup consisting of hydrogen-, alkyl-, ara1kyl-, cycloalkyl-, aryl-, aheterocyclic nucleus,

and substituted derivatives thereof. The broken ring designated as T isthe triazole ring, the structure of the triazole ring in the A compoundsbeing the same as that of compound 14A, and the structure of thetriazole ring in the B compounds being the same as that of Compound 14Bof Flow Sheet C.

FLOW SHEET L O- O Gt, I or,

I OH, I OH,

O' "W R; MNR;

10 (Flow Sheet 0) as o 0- Cg: I Cg: I

I on, H,

--o/ --O/ I: Iuw R I IWI R3 I H ll 0 O wherein R is a member of thegroup consisting of hydrogen-, u-fluoro-, a-methyL, ,B-methylandmethylene-, and R is a member of the group consisting of hydrogen-,alkyl-, ara1ky1-, cycloa1ky1-, aryl-, a heterocyclic nucleus, andsubstituted derivatives thereof. The broken ring designated as T is thetriazole ring, the structure of the triazole ring in the A compoundsbeing the same as that of Compound 60A, and the structure of thetriazole ring in the B compounds being the same as that of Compound 60B.

21 FLOW SHEET M 55 (Flow Sheet K--R| and X are 01) 60 (Flow Sheet L-R1and X are H) Where-in both R and X are hydrogen, or both R and X arech1oro-; R is a member of the group consisting of hydrogen-, a-fiuoro-,a-methyL, B-methyland methylene-,

and R is a member of the group consisting of hydrogen-,

Z alkyl-, ara1kyl-, cycloalkyl-, ary1-, a heterocyclic nucleus, andsubstituted derivatives thereof. The broken ring designated as T is thetriazole ring, the structure of the triazole ring in the A compoundsbeing the same as that of compound 14A, and the structure of thetriazole ring in the B compounds being the same as that of com- F LOWSHEET 0 66 (Flow Sheet N) R is a member of the group consisting of T isthe triazole ring, the structure of the triazole ring in the A compoundsbeing the same as that of Compound 14A, and the structure of thetriazole ring in the B compounds being the same as that of wherein bothR and X are hydrogen-, or both R and X are chloro-;

ignated as FLOW SHEET N R; and X are C1) 61 (Flow Sheet L-Rl and X areH) 54 (Flow Sheet K Compound 14B of Flow Sheet C.

FLOW SHEET P l l CE; Us l OO OO L CHz CHI Rlfl: ]/wv R3 R3 i T X a, O I

67 (Flow Sheet N) 75A db wherein both R and X are hydrogen, or both Rand X are chloro-; R is a member of the group consisting of X hydrogen-,u-fiuoro-, a-methyl-, fl-methyland methyl- 52% ene-, and R is a memberof the group consisting of hywherein both R and X are hydrogen, or bothR and X drogen" alkyl" aralkyl" cycloalkyl', aryl" a heterocychc arech1oro-; R is a member of the group consisting of hynucleus-, andsubstituted derivatives thereof. The broken h fluoroh p g p and 1 ringdesignated as T is the triazole ring, the structure of 5 is a member ofthe group Consisting of hydfogenn the triazole ring in the A compoundsbeing the same alkyl" a q t w he'terocyclic nucleus,

that of com ound 14A and the structure of the and substltutedderivatlves thereof, X 1s a member of the as p group consisting ofhydrogen and halogen and X is a 91016 nng m the compounds bemg the Sameas that member of the group consisting of chloro and fluoro. T ofcompound 14B of Flow Sheet C. 40 is the triazole ring.

FLOW SHEET Q OH CHaF(C1) OH, 01130;; I= l=0 (i=0 OH ---0H --0H ---OH T XT X T X g 83A 84A 85A 83B 84B 85B R: 83C R1 84C R2 850 CHaR CHzR OHgR ii -OH "-OH --o P R; R1 "0H R1 \O/ \Q /g\/ T X T X T X E E i R2 R2 B2 79A83A 84A 93A 94A 79B 83B 84B 93B 94B 79C 83C 84C 93C 940 wherein R is amember of the group consisting of hydro- 0 gen, 115-hydroxy-,llfi-chloroand keto-, but chloro is g g I present at R only when X isehloro, and hydrogen is pres- O 0 ent at R; only when X is hydrogen; Ris a member of l the group consisting of hydrogen-, a-chloro-,a-fluoro-,

a-methyland fi-methyL; R is a member of the group R1 NW R3 R1 W R:consisting of hydrogen-, oc-fllIOI0-, u-methyl-, li-methylandmethylene-; R is a member of the group consisting of hydrogen-,hydroXy-, chloroand fiuoro-; R is a mem- /i /i\/ ber of the groupconsisting of hydrogen-, alkyl-, ara1kyl-, T I j; T cyc1oalkyl-, ary1-,a heterocyclic nucleus, and substituted derivatives thereof; and X is amember of the group consisting of hydrogen and halogen. This Flow Sheetalso 23% 22% includes the M' -analogues of the compounds shown. InCompounds 94A, 94B and 940 P and Q are each selected from the groupconsisting of hydrogen, alkyl and aryl, and together with the carbon towhich they are joined, P wherein both 1 and X are hydrogen, both 1 and Xand Q are cycloalkyl. The broken ring designated as T are C1110K); 3 isa member of the group Consisting of is the triazole ring, the structureof the triazole ring in y n a y w fiy and methylthe A compounds beingthe same as that of compound and 5 18 a member of the group consistingof 7A, the structure of the triazole ring in the B comy aralkyl', y 'y nheterocyclic pounds being the same as that of compound 7B, and thnucleus, and substituted derivatives thereof. T=tristructure of thetriazole ring in the C compounds being azole ringthe same as that ofcompound 70 of Flow Sheet B. OW SHEET S FLOW SHEET R 0 o 0 0 1 C I l C\Q O\ \0 O\ \O-O\ \O O\ L 0H. l on, 0H1 L on, "0/ O/ 5 -O/ O/ R1 NW RaR1 MN R; M a W R;

T I X T X T I T I'IY 1'1 Vii 11 ii 0 OH OH F1 Sh K ana ram as 22%wherein R is a member of the group consisting of hydrogen, a-fluoro,a-methyl, B-methyl, and methylene; R is a member of the group consistingof hydrogen, alkyl, aralkyl, cycloalkyl, aryl, a heterocyclic nucleus,and substituted derivatives thereof. The broken ring designated as T isthe triazole ring, the structure of the triazole ring in the A compoundsbeing the same as that of compound 14A, and the structure of thetriazole ring in the B compounds being the same as that of compound 14Bof Flow Sheet C.

Example 1 The following procedures which relate to Flow Sheet A areparticularly described starting with the 11,8,17a,21-trihydroxy-16a-methyl-4-pregnene-3,20-dione, but are generallyapplicable to all of the starting materials defined by Flow Sheet A.

To a suspension of 25.0 g. of 11/3,17a,21-trihydroxy-16a-methyl-4-pregnene-3,20-dione in 1.5 liter of alcoholfree chloroformcooled to about 5 C. in an ice bath is added with constant stirring 75ml. of cold, concentrated hydrochloric acid and then 750 ml. of formalin(low in methanol). The mixture is removed from the ice bath and stirredat room temperature for 7 hours. The layers are separated and theaqueous phase is back-extracted twice with chloroform. The combinedorganic layers are washed twice with a solution of sodium bicarbonate,and twice with a saturated salt solution. The solution is dried overmagnesium sulfate and evaporated under reduced pressure, to give17u,20,20,21-bis(methylenedioxy)-1lfi-hydroxy-l6a-methyl-4-pregnene-3-one which is used in the subsequentstep of the synthesis without further purification.

A solution of 400 mg. of 17m,20,20,21-bis-(methylenedioxy)-1lfi-hydroxy-l6a-methy1-4-pregnene-3-one in 4 ml. of pyridine is added tothe complex formed by the addition of 400 mg. of chromium trioxide to 4ml. of pyridine. The mixture is swirled until thoroughly mixed and thentflllOWGd to stand at room temperature overnight. The reaction mixtureis poured into water, and the aqueous mixture is extracted with etherand then twice with ethyl acetate. The combined ether and ethyl acetateextracts are washed with dilute aqueous sulfuric acid at about 0 C., andthen water until neutral. The organic solvent layer is then dried, thesolvents are evaporated therefrom under vacuum, and the residualcrystalline material is purified by crystallization from a mixture ofethyl acetate and ether to give 17a,20,20,21-bis(methylenedioxy)-16a-methyl-4-pregnene-3,l l-dione.

Three grams of17u,20,20,21-bis(methylenedioxy)-16amethyl-4-pregnene-3,1l-dione (6.96rnmoles) is dissolved in 150 cc. of benzene with warming. About 30 cc.of the benzene is distilled oif under normal pressure and the solutionis then cooled to room temperature. About 4.5 cc. of ethyl formate (56.1rnmoles), and then 900 mg. (64.5 rnmoles) of a 57% dispersion of sodiumhydride in mineral oil is added. If the reaction does not startimmediately it can be initiated by the addition of 0.5 ml. of 0.5N-methanolic sodium methoxide. After a total of about 2 /2 hours, 50 cc.of water is added carefully with cooling. The reaction mixture isdiluted with ml. of ether and the organic layer is extractedsequentially with four 25 ml. portions of l N sodium hydroxide solutionand 2.5 ml. of 2 N sodium hydroxide solution. The combined aqueousextracts, including the water layer initially separated, are allowed tostand for 15-30 minutes. The extracts are then cooled and carefullyacidified with about 45 ml. of saturated sodium dihydrogen phosphatesolution. The temperature is maintained below 20 C. The aqueoussuspension is extracted with two 1000 ml. portions of ether. The etherlayer is washed with 200 ml. of water and 100 ml. of saturated sodiumchloride solution, dried over sodium sulfate, and concentrated undervacuum to yield 17a,20,20,21-bis(methylenedioxy) 2hydroxymethylene-16u-methyl-44pregnene-3,1 l-dione.

A solution consisting of 1.0 g. of l7a,2(),20,21-bl$(methylenedioxy)-2-hydroxymethylene 16a methyl 4- pregnene-3,11-dione in6 ml. of methylene chloride, 30 ml. of glacial acetic acid and 2 ml. ofwater is cooled in ice. Sodium nitrite (150 mg.) in 7 ml. of water isadded with stirring, and stirring is continued for 30 minutes at 0 C. inan atmosphere of nitrogen. At the end of this time 60 ml. of ice wateris added to the reaction mixture and the produce is extracted withmethylene chloride, washed with water, saturated sodium bicarbonatesolution and sodium chloride solution. The methylene chloride solutionis dried over magnesium sulfate and evaporated to dryness under vacuum.The 17a,20,20,2l-bis(methylenedioxy)-24hydroxyirnino-16a methyl 4pregnene 3,11- dione is recovered by recrystallization.

A mixture of 2.7 g. of 17a,20,20,21-bis(methylenedioxy)-2-hydroxyimino16oz methyl 4 pregnene 3,11- dione, 240 ml. of ethylene glycol and 33ml. of hydrazine monohydrate is refluxed in a nitrogen atmosphere for 4hours. The reaction mixture is cooled to room temperature and 600 ml. ofwater is added. The precipitate formed is collected by filtration. Thefiltrate is extracted continuously for 3 days with chloroform, giving a1.8 g. of a brown foam. The latter is combined with the precipitate andchromatographed on silica gel. The eluates with benzene in ethermixtures affords 17a,20,20,21-bis (methylenedioxy) 16a methyl 11 oxo 4pregneno- [3,2-d]-l',2',3'-triazole, M.P. 281-286 C. (decomposes) a-=+49;

A solution of 300 mg. of17a,20,20,21-bis(rnethylenedioxy)-2-hydroxyimino-l600-methyl 4 pregnene3,11- dione in 9 ml. of ethanol and mg. of phenylhydrazine is allowed tostand at room temperature over night. Water and a benzene ether solution(1:1) are added. The organic layer is extracted twice with 2 Nhydrochloric acid, then, with saturated sodium bicarbonate solution andfinally with water. A brown amorphous material (353 mg.) is obtainedfrom the organic layer. An aliquot (340 mg.) is dissolved in 4 ml. ofbenzene and filtered through acid washed alumina. Elution with 30 ml. ofbenzene yields 17a,20,20,21-bis(methylenedioxy)-2-hydroxyimino-3-phenylhydrazono-16u-methyl-4-pregnene-1l-one.

To an ice cooled solution of 100 mg. of the crude 17a,20,20,21-bis(methylenedioxy) 2 hydroxyimino16amethyl-3-phenylhydrazono-4-pregnene-1l-one in 20* ml. of chloroformand 7 ml. of pyridine is added 300 mg. of phosphorous pentachloride intwo portions. After stirring for 15 minutes the brown solution is heatedto 65 C. for 10 minutes. The cooled reaction mixture is diluted withabout 50 ml. of chloroform and washed sequentially with water two times,2.5 N hydrochloric acid and finally with water to neutrality. The crudematerial is dissolved in 7 ml. of benzene and chromatographed on acidwashed alumina. The 170:,2O,20,2l bis(methylenedioxy)16amethyl-11-oxo-2' phenyl 4 pregneno [3,2-d] 2H- 1',2',3-triazole ispurified by crystallization.

In accordance with the above procedures, but using an equivalentquantity of :any of the other substituted hydrazines listed in column 3,there is obtained the corresponding2-substituted-17a,20,20,21-bis(methylenedioxy)-16amethyl-l1-oXo-4-pregneno-[3,2-d]2H-1',2,3 'triazole.

A solution of 300 mg. of17a,20,20,21-bis(methylenedioxy)-2-hydroxyimino-16a-methyl 4 pregnene3,11- dione in 9 ml. of ethanol and 120 mg. of p-fiuorophenylhydrazineis allowed to stand at room temperature over night. Water and a benzeneether solution (1:1) are added. The organic layer is extracted twicewith 2 N hydrochloric acid, then with saturated sodium bicarbonatesolution and finally with water. A brown amorphous material (353 mg.) isobtained from the organic layer. An aliquot (340 mg.) is dissolved in 4ml. of benzene and filtered through acid washed alumina. Elution withbenzene yields17a,20,20,21-bis(methylenedioxy)-2-hydroxyirnino-3-p-fluorophenylhydrazono-16amethyl 4 pregnene-l l-one.

To an ice cooled solution of 100mg. of the crude 17a,20,20,21-bis(met-hylenedioxy) 2 hydroxyimino 3pfiuorophenylhydrazono'16a methyl-4-pregnene-11-one in 20 ml. ofchloroform and 7 ml. of pyridine is added 300 mg. of phosphorouspentachloride in two portions. After stirring for 15 minutes the brownsolution is heated to 65 C. for 10 minutes. The cooled reaction mixtureis diluted with about 50 ml. of chloroform and washed sequentially withwater two times, 2.5 N hydrochloric acid and finally with water toneutrality. The crude material is dissolved in 7 ml. of benzene andchromatographed on acid washed al mina. The 17a,20,20,21-bis(methylenedioxy)-16u-methyl-11-oxo 2' p fluorophenyl 4pregneno-[3,2-d] -2H-1,2',3-triazole is purified .by crystallization.

The above 17a,20,20,21-bis(methylenedioxy)- derivatives are convertedinto the corresponding 21-hydroxy-, 21-acyloxy-, ZI-phosphates,21-desoxy-, 21-chloroand 21-fluoro-17a-hydroxy-20-oxo 4 pregneno- (or4,6-pregnadieuo)-[3,2-d]-2H-l',2',3-triazole, as well as the saltsthereof, by following the procedures of Examples 18 and 19.

In accordance with the above procedures, but omitting the second step(oxidation of the llfi-hydroxy group to the ll-keto group), thecorresponding llfi-hydroxy-compounds are obtained.

The 21-hydroxy-, 21-chloro-, 21-fluoro-, and 21-desoxysteroids, whereinH is present at the 16-position, are converted into the16a,17a-dihydroxy-steroids and the 1605, 17a-acetals and ketals thereoffollowing the procedures of Example 24.

Example 2 The following procedure which relates to Flow Sheet B isparticularly described starting with the 17a,2;0,20,21-bis(methylenedioxy)-16u-methyl-11 oxo 4 pregneno-[3,2-d]-1',2,3'-triazole, but is generally applicable to all thestarting materials defined by Compound 6 of Flow Sheet B.

A solution of about 0.47 millimole of 17o,2(),20,21- bis(methylenedioxy)16a methyl-lloxol-pregneno- [3,2-d]-1',2',3'-triazole in 10 ml. ofbenzene is treated with about 30-38 mg. of about 51% sodium hydride (inoil suspension). After the addition of 2-3 ml. of dimethylformamide(dried over calcium hydride) and 5 ml. of methyl iodide, the mixture isstirred at room temperature over night. The product is filtered, washedwith methylene chloride, and the filtrate and washings are taken todryness. The residue is treated with water and the product is filteredto afford a mixture of the 1-methyl-17a,20,20,21-bis(methylenedioxy)-16a-methy-l 11 oxo- 4-pregneno-[3,2-d]1H-1,2',3-triazole, 2-methyl-17a, 20,20,21 bis(methylenedioxy) 16o:methyl-11-oxo-4- pregneno [3,2-d] 2'H-l',2',3-triazole, 3-methyl-17a,20,20,21 bis(methylenedioxy)-16a-methyl 11 oXo-4-pregneno-[3,2-d]-3H-1',2,3' triazole. The mixture is separated bychromatography.

In accordance with the above procedure, but using another alkylatingagent, for example, ethyl iodide, propyl iodide and the like, in placeof the methyl iodide, there is obtained the corresponding1-alkyl-17a,20,20,2l-bis- (methylenedioxy)-16ot-methyl 11oxo-4-pregneno-[3,2- d]-1'H-1,2',3'-t-riazole, 2-a1kyl17a,20,20,21-bis-(methylenedioxy)-16ot-metl1yl-l1-oxo-4-pregneno [3,2-d]-2'H- l',2',3-triazole, or3-a1kyl-17a,20,20,21-bis(methylenedioxy)-16a-methyl 11oxo-4-pregneno-[3,2-d]-3H-1,2', 3'-triazole.

In accordance with the above procedure, but starting with thellfi-hydroxy-analogue, the corresponding 1-alkyl-17a,20,20,21-bis(methylenedioxy) 11 3 hydroxy- 16ot-methyl 4pregneno [3,2-d]-1'H-1',2,3-triazole, 2'-alkyl-17a,20,20,21bis(methylenedioxy)-11/3-hydroxy-16u-methyl-4-pregneno-[3,2-d]-2H-1',2',3' triazole, and3'-alkyl-17ot,20,20,21 bis(methylenedioxy)-1lfi-hydroxy- 16amethyl-4-pregneno-[3,2-d]-3H-1',2,3-triazole are obtained.

The above 17a,20,20,21 bis(methylenedioxy)-derivatives are convertedinto the corresponding 21-hydroxy-, 21-acyloxy-, 21-phosphates-,21-desoxy-, 2l-chloroand 2l-fluoro-17u-hydroxy-20-oxo-4-pregneno- (or4,6-pregnadieno)-[3,2-d]-1',2',3'-triaz0le, as well as the saltsthereof, by following the procedures of Examples 18 and 19.

Example 3 The following procedures which relate to Flow Sheet C areparticularly described starting with the 17oc,21dihydroxy-l6a-methyl-4-pregnene-3,11,20-t rione, but are generallyapplicable to all the starting materials defined in Flow Sheet CCompound 8.

Twenty-four grams of l7zx,21-dihydroxy-l6u-methyl-4-pregnene-3,11,20-trione, 910 ml. of chloroform, 237 ml. of concentratedhydrochloric acid and 237 ml. of 37% formaldehyde are combined andstirred at room temperature for 70 hours. The chloroform layer isseparated, and the aqueous layer is extracted 2 times with 50 ml.portions of chloroform. The combined chloroform solutions are thenWashed sequential-1y with two 200 ml. portions of water, 200 ml. ofsaturated sodium bicarbonate solution and 200 ml. of water. Thechloroform solution is dried over magnesium sulfate and thenconcentrated under vacuum. The product, which is the 1704,20,20,21-bis(methylenedioxy)-l6u-methyl 4 pregnene- 3,11-dione, isobtained by crystallization from methanol.

The 17a,20,20,21 bis(methylenedioxy)-l6a-methyl-4- pregnene-3,11-dione(17.5 g.) is dissolved in 890 ml. of benzene. Then 45 ml. of ethyleneglycol and 1.78 g. of p-toluenesulfonic acid monohydrate is added. Themixture is heated at reflux with stirring to about 17.5 hours, whilecontinuously collecting the water which forms. The solution is cooled to20 C. and washed sequentially with two 200 ml. portions of water, 200ml, of saturated sodium bicarbonate solution and 200 ml. of water. Thewashes are back extracted with benzene, and the henzene extract is addedto the batch. The dried benzene solution is concentrated to drynessunder vacuum to give a mixture of crystals and oil. The mixture isrefluxed with ml. of ether for /2 hour. It is then cooled,

31 filtered and washed with cold ether to afford the 17a,20, 20,21bis(methylenedioxy)-3-ethylenedioxy-16ot-methyl- 5-pregnene-1 l-one.

A solution of 22.9 grams of17a,20,20,21-bis(methylenedioxy)-3-ethylenedioxy 16amethyl-S-pregnene-llone in 200 ml. of benzene is added to 460 ml. ofperbenzoic acid (0.325 M) over a time period of approximately 30 minuteswhile keeping the temperature at 20 25 C., the perbenzoic acid solutionhaving been dried over magnesium sulfate prior to use. After 48 hours atroom temperature the titre indicates that about 120% of the theoreticalamount of perbenzoic acid has been consumed. The solution is cooled to10 C. and a 15% solution of sodium bisulfite cooled to a temperature ofless than 20 C. is added with good agitation until a negative potassiumiodide test is obtained. The aqueous phase is removed and the benzene iswashed with 5% sodium bicarbonate solution until it is acid free, and isthen washed with water. After drying, the benzene is concentrated undervacuum to yield a mixture of the c and B isomers of l7u,20,20,21bis(methylenedioxy) 5,6-epoxy-S-ethylenedioxy-l6a-methyl-5a-pregnane-1l-one in a ratio of about6:4. The isomers are separated by chromatography on Florisil (anactivated magnesium silicate made according to U.S. Patent 2,393,625).The a-isomer is obtained by elution with acetone in hexane and thenrecrystallizing from a mixture of benzene and hexane.

The l7ot,20,20,2l-bis(methylenedioxy) 504,60: epoxy-3-ethylenedioxy-l6ot-methyl 50c pregnane-ll-one is dissolved in 300 cc.of 98100% formic acid at room temperature and allowed to stand for 2.5hours. The solution is poured into water and extracted with chloroform.The chloroform solution is washed with saturated aqueous sodiumbicarbonate solution, dried over sodium sulfate and concentrated undervacuum. The crude mixed formates are dissolved in 1400 cc. of methanol,refluxed for one-half hour under nitrogen :with a solution consisting of27 g. of potassium hydroxide and 135 cc. of water. The cooled solutionis neutralized with 37 cc. of acetic acid and concentrated under vacuumat 30 C. The resulting solution is poured into water and extracted withchloroform. The chloroform layer is washed with aqueous sodiumbicarbonate solution, dried over sodium sulfate and concentrated undervacuum. Crystallization from methanol gives the17a,20,20,21-bis(methylenedioxy)-16ot-methyl-5a-pregnane-3 ,6,11-trione.

A solution consisting of 8.0 grams of 17oc,20,20,21-bi$-(methylenedioxy) 16cc methyl-a-pregnane-3,6,1l-trione, and 8 ml. ofmorpholine in 80 ml. of benzene is refluxed vigorously for 1 hour in thepresence of Linde molecular sieves contained in a Soxhlet extractor. Thesolution is cooled and concentrated. Crystallization from a mixture ofethyl acetate and ether affords the 17OL,20,20, 21-bis(methylenedioxy)16ot-methyl-3-morpholine-5a,2- pregnene-6,1 l-dione.

A solution consisting of 2.1 g. of 17a,20,20,21-biS- (methylenedioxy)16cc methyl-3-morpholino-5a,2-pregnene-6,l1-dione and 1.5 ml. of phenylazide in 30 ml. of benzene is refluxed over night to form a mixture of 1and 3-phenyl 17a,20,20,21 bis(methylenedioxy)-16u-methyl-6,11-dioxo 50cpregnano-[3,2-d]-3H-1,2'-3-triazole. The solution is concentrated undervacuum and chromatographed on 100 g. of acid washed alumina. Elutionwith chloroform and ethyl acetate and crystallization from chloroformand ethyl acetate affords the 3-phenyl-derivative, M.P. 350 C; +5 (C.1.0 CHCl U.V. m2? 228 m In accordance with the above procedure, butreacting with the p-fluorophenyl-azide the correspondingp-fluorophenyl-derivatives are obtained.

The above 17u,20,20,21-bis(methylenedioxy) derivatives are convertedinto the corresponding 2l-hydroxy-,

21-acyloxy-, 21-phosphates-, 21-desoxy-, 2l-chloroand 21fluoro-17a-hydroxy-20-oxo-3-phenyl-4-pregneno- (or4,6-pregnadieno)-[3,2-d]-3H-1,2,3'-triazoles, as well as the saltsthereof, by following the procedures of Examples 18 and 19.

The 21-hydroxy-, 21-chloro-, 2l-fluoro-, and 2l-desoxysteroids, whereinH is present at the 16-position, are converted into the16a,17u-dihydroxy-steroids and the 16:1, 17a-acetals and ketals thereoffollowing the procedures of Example 24.

Example 4 The following procedures which relate to Flow Sheet D areparticularly described starting with the 17a,20,20,2lbis(methylenedioxy)3 phenyl-16m-methyl-6,1l-dioxo- 5ot-pregnano-[3,2-d]-3H-1,2,3'-triazole,but are generally applicable to all compounds defined by Flow Sheet D(Compounds 14A and 14B).

A solution of 500 mg. of17a,20,20,21-bis(methylenedioxy)-16a-methyl-3-phenyl 6,11dioxo-5a-pregnano- [3,2-d]-3H-l',2',3-triazole in 35 ml. oftetrahydrofuran which has been freshly distilled from lithium aluminumhydride, and a solution of 750 mg. of sodium borohydride in 4 ml. ofwater are purged 6 times with nitrogen and then the solutions arecombined. After stirring at room temperature under nitrogen for onehour, the combined solution is cooled to 0-5 C. and a saturated solutionof 4.7 grams of monobasic sodium phosphate is added over a time periodof approximately 15 minutes. The reaction mixture is stirred for anadditional 15 minutes. The slurry is then concentrated under vacuumkeeping the temperature below 25 C. until the tetrahydrofuran isessentially removed. The slurry is cooled, filtered and washed withwater until neutral. The product is the 20,20,2l-bis(methylenedioxy) 6,8hydroxy-16a-methyll1-oxo-3'-phenyl-5a-pregnano [3,2-d]3H-1,2,3-triazole.

A solution of thionyl chloride in pyridine is prepared by adding 7.5 cc.of freshly distilled thionyl chloride to 38 cc. of ice-cold anhydrouspyridine. This is added dropwise to a stirred solution of 7.0 g. of17a,2(),20,2l-bis- (methylenedioxy) 65 hydroxy 16a-methyl-11-oxo-3'-phenyl-5a-pregnano-[3,2-d]-3'H-1,2,3'-triazole in 45 cc. of anhydrouspyridine. The rate of addition is controlled such that the reactionmixture is maintained at approximately 40 C. The solution is stirred anadditional 30 minutes after the addition of the reagent is completed,subsequently cooled in ice and poured into 250 cc. of icewater. Themixture is extracted with chloroform and the chloroform layer is washedwith aqueous sodium bicarbonate solution, dried over sodium sulfate andconcentrated under vacuum. The crude product, dissolved in benzene, ischromatographed on silica gel. Elution with ether-petroleum ether, andether-chloroform mixtures affords 17a,20,20,2l bis(methylenedioxy)16ozmethyl 11 oxo-3'-phenyl-5-pregneno-[3,2-d1-3'H-1', 2',3-triazole.

A solution consisting of 0.45 g. of the above steroid product in 28 ml.of chloroform, saturated with dry hydrogen chloride is allowed to standat room temperature for 6 hours. The reaction mixture is diluted withchloroform and poured into ice water. The chloroform layer is separated,Washed with water and sodium bicarbonate solution, dried andconcentrated under vacuum. Chromatography on acid washed alumina affordsthe 170;,20, 20,21-bis(methylenedioxy) 16amethyl-11-oxo-3'-phenyl-4-pregneno-[3,2-d]-3H-l',2,3'-triazole.

A solution of 500 mg. of the above product in 35 ml. of tetrahydr-ofuranwhich has been freshly distilled from lithium aluminum hydride, and asolution of 750 mg. of sodium borohydride in 4 ml. of water are purged 6times with nitrogen and then the solutions are combined. After stirringat room temperature under nitrogen for 18 hours, the combined solutionis cooled to 05 C. and a saturated solution of 4.7 grams of monobasicsodium phosphate is added over a time period of approximately 15minutes. The reaction mixture is stirred for an additional 15 minutes.The slurry is then concentrated under vacuum keeping the temperaturebelow 25 C. until the tetrahydro furan is essentially removed. Theslurry is cooled, filtered and Washed with water until neutral. Theproduct is 170:, 20,20,21 bis(methylenedioxy)-1lfl-hydroxy-l6a-methyl- 3'-phenyl-4-pregneno- [3 ,2-d] -3 'H- 1 ',2,3 '-triazole.

Example 5 The following procedures which relate to Flow Sheet E areparticularly described starting with the 17a,20,20,21-bis(methylenedioxy) 3 phenyl-l6a-rnethyl-6,ll-dioxo-Sa-pregnano-[3,2-d]-3'H-1',2',3-triazole but are generally applicable toall steroids defined by compounds 14A and 14B of Flow Sheet E.

A solution containing 3 cc. of methyl iodide in cc. of ether is added,with stirring, to 300 mg. of magnesium covered with 10 cc. of ether.After the magnesium is consumed an additional 20 cc. of ether is added.To this solution is added with stirring over a period of 10 minutes asolution consisting of 2.91 g. of the 17a,20,20,21- bis(methylenedioxy)16a methyl-6,11-dioxo-3'-phenyl- 5u-pregnano-[3,2-d]-3H-'1,2,3'-triazoleof Example 3 in 40 cc. of benzene. The suspension is'allowed to stir foran additional half hour and is then decomposed with 40 cc. of Water.After the addition of 100 cc. of benzene, the layers are separated, andthe aqueous layer is extracted twice with 100 cc. of chloroform. Theorganic layers are combined, dried over sodium sulfate and concentratedunder vacuum. Chromatography on silica gel and elution withether-petroleum ether and ether-chloroform mixtures affords the17a,20,20,21-bis (methylenedioxy) -6fl-hydroxy- 60:,16u dimethyl1l-oxo-3'-phenyl-5a-pregnano-[3,2-d]- 3H-l',2,3-triazole.

A solution of thionyl chloride in pyridine is prepared by adding 7.5 cc.of freshly distilled thionyl chloride to 38 cc. of ice-cold anhydrouspyridine. This is added dropwise to a stirred solution of 7.0 g. of17oc,20,20,21-bi$ (methylenedioxy) 66 hydroxy-6u,l6a-dimethyl-1l-oxo-3'-phenyl-5a-pregnano-[3,2-d]-3H-1,2',3'-triazole in 45 cc. of anhydrouspyridine. The rate of addition is controlled such that the reactionmixture is maintained at approximately 40 C. The solution is stirred anadditional 30 minutes after the addition of the reagent is completed,subsequently cooled in ice and poured into 250 cc. of ice-water. Themixture is extracted with chloroform and the chloroform layer is Washedwith aqueous sodium bicarbonate solution, dried over sodium sulfate andconcentrated under vacuum. The crude product dissolved in benzene, ischromatographed on silica gel. Elution with ether-petroleum ether, andether-chloroform mixtures affords the 17u,20,20,2l bis(methylenedioxy)6,16u-dimethyl 11-oxo-3-phenyl-5-pregneno-[3,2-d] -3H-1,2,3- triazole.

A solution consisting of 520 mg. of the above product and about 500 mg.of selenium dioxide in 35 ml. of butanone dioxolane is refluxed for 3-5hours. The cooled solution is filtered, washed with aqueous sodiumcarbonate solution, dried and concentrated under vacuum. Crystallizationfrom ethyl acetate affords the 17a,20,20,21-bis (methylenedioxy)4i-hydroxy-6,16u-dirnethyl-11-oxo-3'- phenyl-S-pregneno- [3 ,2-d] -3H-1,2,3 -triazole.

A solution of 500 mg. of the above product in 35 ml. of tetrahydrofuranwhich has been freshly distilled from lithium aluminum hydride, and -asolution of 750 mg. of sodium borohydride in 4 ml. of water are purged 6times with nitrogen and then the solutions are combined. After stirringat room temperature under nitrogen for 18 hours, the combined solutionis cooled to 0-5 C. and a saturated solution of 4.7 grams of monobasicsodium phosphate is added over a time period of approximately minutes.The reaction mixture is stirred for an additional 15 minutes. The slurryis then concentrated under vacuum keeping the temperature below 25 C.until the tetrahydro- 34 furan is essentially removed. The slurry iscooled, filtered and washed with water until neutral. The product is1701, 20,20,21 bis(methylenedioxy) 4,11/3-dihydroxy-6,16adimethyl 3'phenyl-S-pregneno-[3,2-d]-3'H-1',2,3-triazole.

A suspension containing mg. of the above product, and 8 cc. of 60%aqueous formic acid is heated inside a steam cone for 40 minutes. Theresulting solution is cooled and extracted with chloroform. Thechloroform layer is washed with aqueous sodium bicarbonate solution,dried over sodium sulfate and concentrated under vacuum. The crudeconcentrate is dried by azeotropic distillation with benzene :and thensubsequently treated for 15 minutes with 0.7 milliequivalents of sodiummethoxide in 1.0 ml. of methanol in water to cleave any for mate esters.Isolation by partition chromatography affords the1lB,l7a,21-trihydroxy-6,16a-dime-thyl-20-oxo-3-pheny-l-4,6-pregnadieno-[3,2-d]-3H 1,2,3 triazole. Afterneutralization of the above product with acetic acid the solution isdiluted with water and extracted with chloroform. The chloroform layeris dried over sodium sulfate and concentrated under vacuum. The materialis acetylated with acetic anhydride in pyridine, and chromatographed onsilica gel. The column is eluted with ether chloroform mixtures toobtain the 11/3,17oz,21-tI-1 hydroxy 6,16ocdimethyl-20-oxo-3'-phenyl-4,6-pregnadieno-[3,2-d]-3H-1,2,3-triazole21-acetate. V

The 11B,17u,21-trihydroxy 6,16a dimethyl-ZO-oxo- 3-phenyl 4,6pregnadieno-[3,2-d]-3H-l',2',3'-triazole is converted into thecorresponding 2l-desoxy-, 21-fluoro-, 21-chloro-, and 21-phosphatecompounds, as well as the salts thereof following the procedures ofExampes 18 and 19.

The 21-hydroxy-, 21-chloro-, 2l-fluoro-, and 2l-desoxysteroids, whereinH is present at the 16-position, are converted into the16a,17a-dihydroxy-steroids and the 16a,17a-acetals and ketals thereoffollowing the procedures of Example 24.

Example 6 The following procedures which relate to Flow Sheet F areparticularly described starting with the 17a,20,20,21-bis(methylenedioxy) 16a methyl-11-oxo-3'-phenyl-5-pregneno-[3,2-d]-3'H-1',2,3'-triazole, but are generally applicable toall starting materias defined by compounds 16 and 46 of Flow Sheet F.

A solution containing 16.5 g. of 17oc,20,20,21-bi$ (methylenedioxy) 16amethyl-1l-oxo-3'-phenyl-5-preg neno-[3,2-d]-3H-1',2,3-triazole ofExample 4 and 45 milliequivalents of perbenzoic acid in a total volumeof 350 ml. of benzene is stirred in the dark at room temperature for 45hours. The reaction mixture is washed with saturated aqueous sodiumbicarbonate solution and dried over sodium sulfate. The product is thenconcentrated under vacuum to yield the17a,20,20,21-bis(methylenedioxy)-Sa,6a-epoxy 16ozmethyl-11-oxo-.3-phenylpregnano- 3,2-d] -3 'H- l ,2,3 '-triazole, afterpurification.

To a solution of mg. of the above product in 4 ml. of chloroform isadded 5 ml. of concentrated hydrochloric acid. The two-phase mixture isstirred at 25 C. for 1 hour. Addition of water and chloroform extractiongives the 17a,20,20,21-b1$(mBthYl6n6dlOXY)-6,8-Ch10-ro-5a-hydroxy-l6a-methyl 11 oxo-3'-phenyl-pregnano-[3,2-d]-3'H-1',2,3-triazole.

To a solution of 200 mg. of17a,20,20,2l-bis(methylenedi-oxy)-5a,6a-epoxy 16amethyl-l1-oxo-3-phenylpregnano-[3,2-d]-3'H-1,2,3-triazole in 2 ml. ofchloroform and 2 ml. of tetrahydrofuran in a polyethylene bottle at 60C. is added 2 ml. of 2:1 (by weight) mixture of anhydrous hydrogenfluoride and tetrahydrofuran. After 4 hours at -10 C. the mixture iscooled to 60 C. and cautiously added to a stirred mixture of 30 ml. of25% aqueous potassium carbonate and 25 ml. of chloroform kept at -5 C.The aqueous phase is further extracted with chloroform and the latterphase is minutes.

35 washed with water and dried over magnesium sulfate. The residue oncrystallization from a mixture of acetone and ether gives the17a,20,20,21-bis(methylenedioxy)-6[3- A solution of thionyl chloride inpyridine is prepared by adding 7.5 cc. of freshly distilled thionylchloride to 38 cc. of ice-cold anhydrous pyridine. This is addeddropwise to a stirred solution of 7.0 g. of17a,20,20,2lbis(rnethylenedioxy) 6,8 chloro a hydroxy-16amethyl-ll-oxo 3phenyl-pregnano-[3,2-d]-3H-1,2',3- triazole in 45 cc. of anhydrouspyridine. The rate of addition is controlled such that the reactionmixture is maintained at approximately 40 C. The solution is stirred anadditional 30 minutes after the addition of the reagent is completed,subsequently cooled in ice and poured into 250 cc. of ice-water.

' graphed on silica gel. Elution with ether-petroleum ether, andether-chloroform mixtures affords 17a,20,20,21-bis (methylenedioxy) 6Bchloro 16a methyl-11-oxo-3- In accordance with the above procedure, butusing the the 6fl-fiuoro-derivative instead of the 6fl-chloro-deriva-'tive, the corresponding6,8-fluoro-17a,20,20,21-bis(methylenedioxy)-16a-methyl-11-oxo-3-phenyl 4pregneno- [3,2-d]-3H-1,2',3-triazole is obtained.

A suspension of the 17a,20,20,21-bis(methylenedioxy)- 6B-chloro 16amethyl-11-oxo-3-phenyl-4-pregneno- [3,2-d]-3H-1',2',3'-triazole (11.1g.) and chloranil (24.3 g.) in 360 ml. of dry t-butanol is heated underreflux for three hours, protected by a blanket of nitrogen. The solventis removed and the residue is dissolved in chloroform. The resultingsolution is washed successively with 10% aqueous sodium bisulfitesolution, 5% potassium hydroxide, and then water. The solution is driedover sodium sulfate and concentrated under reduced pressure to give17a,20,20,21-bis(methylenedioxy)- 6-chloro-l6a-methyl 11 oxo 3'phenyl-4,6-pregnadieno- [3,2-d] -3'H-l',2,3 -triazole.

In accordance with the above procedure, but using the 63-fluoro-derivative in place of the 6 3-chloro-derivative, there isobtained the 17u,20,20,21-bis(methylenedioxy)- 6-fluoro 16amethyl-l1-oxo-3-phenyl-4,6-pregnadieno- [3,2-d]-3H-1',2,3'-triazo1e.

A solution of 500 mg. of the 17a,20,20,2l-bis(methyl- 'enedioxy) 6,8chloro-16a-methyl-1l-oxo-3'-phenyl-4-pregneno-[3,2-d]-3H-l,2',3-triazole in 35 ml. of tetrahydrofuran whichhas been freshly distilled from lithium aluminum hydride, and a solutionof 750 mg. of sodium borohydride in 4 ml. of water are purged 6 timeswith nitrogen and then the solutions are combined. After stirring atroom temperature under nitrogen for 18 hours, the combined solution iscooled to 05 C. and a saturated solution of 4.7 grams of monobasicsodium phosphate is added over a time period of approximately Thereaction mixture is stirred for an additional 15 minutes. The slurry isthen concentrated under vacuum keeping the temperature below C. untilthe tetrahydrofuran is essentially removed. The slurry is cooled,filtered and washed with water until neutral to afford the17a,20,20,21-bis(methylenedioxy)-61S-chloro- In accordance with theabove procedure, but using the 6B-fiuoro-derivative instead of the6B-chloro-derivative, there is obtained the17a,20,20,21-bis(methylenedioxy)-6fi-fiuoro-1lp-hydroxy-l6a-methyl-3-phenyl-4 pregneno- [3,2-d]-3'H-1,2', 3'-triazole..

In accordance with the above procedure, but starting with thecorresponding A -compounds there is obtained 36 the 6-chloro-, or6-fluoro 17oc,20,20,21 bis(methylenedioxy)-11/3-hydroxy-16a-methyl-3'phenyl 4,6 pregnadieno-[3,2-d]-3H-l,2,3-triazo1e respectively.

The above 17a,20,20,21-bis(methylenedioxy) derivatives are convertedint-o the corresponding 21-hydroxy-, 21-acyloxy-, 21-phosphate,2l-desoxy-, 21 chloroand 21- fiuoro-17a-hydroxy-20oxo-4 pregneno- (or4,6 pregnadieno)-[3,2-d]-3H-1,2,3'-triazole, as well as the saltsthereof, by following the procedures of Examples 18 and 19.

The 21-hydroxy-, 21-chloro-, 21-fluoro-, and 21-des-oxysteroids, whereinH is present at the 16-position, are converted into the16m,17a-dihydroxy-steroids and the 1611, 17a-acetals and ketals thereoffollowing the procedures of Example 24.

Example, 7

The following procedures which relate to Flow Sheet G are particularlydescribed starting with the 17a,20,20,21-bis(methylenedioxy)-16u-methyl-1l oxo 3' phenyl 5-pregneno-[3,2-d]-3'H-1',2',3-triazole, but are generally applicable toall starting materials defined by Compounds 16 and 46 of Flow Sheet G.

The 17u,20,20,21-bis(methylenedioxy)-16a-methyl-11-oxo-3-phenyl-5-pregneno-[3,2-d]-3H-1,2',3' triazole of Example 4 (1.0g.) in 20 ml. of methylene chloride is added to a stirred mixtureconsisting of 2.6 grams anhydrous hydrogen fluoride, 2.0 grams of leadtetraacetate and 10 ml. of methylene chloride at 75 C. The reactionmixture is maintained at this temperature for about minutes and pouredinto an iced cold mixture of aqueous sodium carbonate and chloroform.The mixture is filtered and the organic layer is dried and concentrated.The residue is chromatographed on acid washed alumina to yield17a,20,20,21-bis(methylenedioxy)-5a,6a-difluoro-16a-methyl-11-oxo-3'-phenyl-pregnano-[3,2-d]-3'H 1,2', 3-triazole.

A solution consisting of 500 mg. of the above product and 350 mg. ofphenyliodosodichloride in 20 m1. of anhydrous chloroform is allowed tostand for 3 hours at room temperature. The solution is washed with waterand aqueous sodium bicarbonate solution, dried and concentrated undervacuum. Chromatography on acid washed alumina affords the17a,20,20,21-bis(methylenedioxy)-5u,6a-dichloro-16a-methyl 11 oxo 3'phenylpregnano-[3,2-d]-3H-1,2,3'-triazole.

The above product (1.0 g.) dissolved in 50 ml .of methanol is refluxedfor 15 minutes with 1 g. of potassium hydroxide dissolved in 5 ml. ofwater. The solution is neutralized with acetic acid and concentrated toa small volume. The product is then taken up in chloroform and thechloroform layer is Washed with water, dried and concentrated undervacuum. Chromatography on acid Washed alumina affords the17a,20,20,21-bi$- (methylenedioxy)-6a-chloro 16a methyl 11 oxo 3'-phenyl-4-pregneno-[3,2-d]-3H-1',2',3'-triazole.

In accordance with the above procedure, but starting with thecorresponding 5a,6a-difluoro-derivative, there is obtained the17u,20,20,2l-bis(methylenedioxy)-6a-fiuoro-16a-methyl-11-oxo-3-phenyl-4-pregneno-[3,2-d]-3H 1', 2',3-triazole.

A solution of 500 mg. of the above product in ml. of tetrahydrofuranwhich has been freshly distilled from lithium aluminum hydride, and asolution of 750 mg. of sodium borohydride in 4 ml. of water are purged 6times with nitrogen and then the solutions are combined. After stirringat room temperature under nitrogen for 18 hours, the combined solutionis cooled to 0-5 C., and a saturated solution of 4.7 grams ofmonobasicsodium phosphate is added over a time period of approximately 15minutes. The reaction mixture is stirred for an additional 15 minutes.The slurry is then concentratedunder vacuum keeping the temperaturebelow 25 C. until the tetrahydrofuran is essentially removed. The slurryis cooled, filtered and washed with water until neutral.

37 The product is 17a,20,20,21 bis(methylenedioxy)6achloro-l1fl-hydroxy-16a-methyl-3' phenyl 4 pregneno-[3,2-d]-3'H-1,2',3'triazole.

In accordance with the above procedure, but starting with thecorresponding 6a-fluoro-derivative there is obtained the17u,20,20,21-bis(methylenedioxy)-6a -fluoro- 11,B-hydroxy-16a-methyl-3'-phenyl-4-pregneno [3,2 d]- 3H-l,2',3-triazole.

The above 17al20,20,21-bis(methylenedioxy)-derivatives are convertedinto the corresponding 21-hydroxy-, 21-acyloxy-, 21-phosphates-,21-desoxy-, 21-chloroand 2 l-fiuoro-17a-hydroxy-20-oxo-4-pregneno- (or4,6-pregnadieno)-[3,2-d]-3H-1',2,3'-triazoles, as well as the saltsthereof, by following the procedures of Examples 18 and 19.

Example 8 The following procedures which relate to Flow Sheet H areparticularly described starting with the 17u,20,20,21-bis(methylenedioxy)-5a,6a-epoxy-16a-methyl-11 x0- 3 -phenyl-pregnano-[3,2-d] -3H-1',2',3 '-triazole, but are general-1y applicable to allstarting materials defined by Compound 24 of Flow Sheet H.

To a solution of 250 mg. of17u,20,20,21-bis(me-thylenedioxy)-u,6a-epoxy-l6u-methyl-11 oxo 3'phenylpregnano-[3,2-d]-3'H-1',2,3'-triazole (Example 6) in 16 ml, of drybenzene under a nitrogen atmosphere is added 2.33 ml. of 3 Mmethylmagnesium bromide in ether. The mixture is heated at 70 C. undernitrogen for 5 hours. After cooling to 05 C., 5.6 g. of ammoniumchloride in 56 ml. of water is added over a time period of approximatelyminutes. The benzene is separated and the aqueous layer is extracted twotimes with 20 ml. of benzene. The combined benzene layers are washedneutral with water, dried with magnesium sulfate and concentrated todryness to give the 17u,20,20,21-bis(methylenedioxy)-5u-hydroxy-6B,16adimethyl 11 oxo-3' phenylpregnano-[3,2-d]-3H-1,2',3'-triazole. The crudeproduct can be used for the next reaction, or it may be firstcrystallized from an organic solvent.

A solution of thionyl chloride in pyridine is prepared by adding 7.5 cc.of freshly distilled thionyl chloride to 38 cc. of ice-cold anhydrouspyridine. This is added dropwise to a stirred solution of 7.0 g. of17a,20,20,21-biS- (methylenedioxy) 5oz hydroxy 65,160: dimethyl 11-oxo-3-phenyl-pregnano-[3,2-d]-3H-1,2,3'-triazole in 45 cc. of anhydrouspyridine. The rate of addition is controlled such that the reactionmixture is maintained at approximately 40 C. The solution is stirred anadditional minutes after the addition of the reagent is completed,subsequently cooled in ice and poured into 250 cc. of ice-water. Themixture is extracted with chloroform and the chloroform layer is washedwith aqueous sodium bicarbonate solution, dried over sodium sulfate andconcentrated under vacuum. The crude product, dissolved in benzene, ischromatographed on silica gel. Elution with ether-petroleum ether, andether-chloroform mixtures affords the17a,20,20,21-bis(methylenedioxy)-6/8,16a-dimethyl-11-oxo-3-phenyl-4-pregneno-[3,2-d]3H 1' ,2, 3-triazole.

The above product (1.0 g.) dissolved in 50 ml. of methanol is refluxedfor 15 minutes with 1 g. of potassium hydroxide, dissolved in 5 m1. ofwater. The solution is neutralized with acetic acid and concentrated toa small volume. The product is then taken up in chloroform and thechloroform layer is washed with water, dried and con centra-ted undervacuum. Chromatography on acid washed alumina afiords the 17 a,20,20,21-bis(methylenedioxy)-6a,16a-dimethyl 11 oxo-3' phenyl 4 pregneno-[3,2-d]-3'H-1',2',3-triazole.

A solution of 500 mg. of the above product in ml. of tetrahydrofuranwhich has been freshly distilled from lithium aluminum hydride, and asolution of 750 mg. of sodium borohydride in 4 ml. of water are purged 6times with nitrogen and then the solutions are combined.

After stirring at room temperature under nitrogen for 18 hours, thecombined solution is cooled to 0-5 C., and a saturated solution of 4.7grams of monobasic sodium phosphate is added over a time period ofapproximately 15 minutes. The reaction mixture is stirred for anadditional 15 minutes. The slurry is then concentrated under vacuumkeeping the temperature below 25 C. until the .tetrahydrofuran isessentially removed. The slurry is cooled, filtered and washed withWater until neutral. The product is the17a,20,20,21-bis(methylenedioxy)-1lfl-hydroxy-6a,16u-dimethyl-3-phenyl 4pregneno [3,2-d]- 3'H-1',2',3'-triazole.

In accordance with the above procedure, but starting with thecorresponding 6/3-methyl-derivative, the corresponding17a,20,20,21-bis(methylenedioxy)-1 1 fi-hydroxy-6B,16a-dimethyl-3-phenyl-4 pregneno [3,2-d] 3H-1, 2',3'-triazole isobtained.

The above 17a,20,20,21-bis(methylenedioxy)-derivatives are convertedinto the corresponding 21-hydroxy-, 21-acyloxy-, 21-phosphates-,21-desoxy-, 21-chloroand 21-fiuoro-17tx-hydroxy-20-oxo-4-pregneno- (or4,6-pregnadieno)-[3,2-d]-2H-1',2,3'-triazole, as well as the saltsthereof, by following procedures of Examples 18 and 19.

The 21-hydroxy-, 21-chloro-, 21-fluoro-, and 21-desoxysteroids, whereinH is present at the 16-position, are converted into the16a,17a-dihydroxy-steroids and the 160:, 17a-acetals and ketals thereoffollowing the procedures of Example 24.

Example 9 The following procedures which relate to Flow Sheet I areparticularly described starting with the 17a,20,20,21-bis(methylenedioxy)-6/3-hydroxy-16o methyl 11 oxo-3'-phenyl-5a-pregnano-[3,2-d]-3H 1',2,3 triazole, but are generallyapplicable to all starting materials defined by Compound 15 of FlowSheet I.

To a solution of mg, of17a,20,20,21-bis(methylenedioxy)-6B-hydroxy-16a-methyl-1l-oxo 3phenyl-5apregnano-[3,2-d]-3H-1,2,3-triazole (Example 4) in 2 ml. ofpyridine is added 0.5 ml. of acetic anhydride. The mixture is allowed tostand over night at room temperature. A mixture of ice and water is thenadded. After standing for about 30 minutes, the product is extractedwith ethyl acetate. The ethyl acetate extract is washed successivelywith water, ice-cold 1 N sulfuric acid (until the pH of the aqueouslayer is 1-3), saturated aqueous sodium bicarbonate (until the pH of theaqueous layer is 8), and water (until the aqueous layer is neutral). Theethyl acetate solution is dried with anhydrous sodium sulfate. Thesolvent is then distilled at about 40 C. under vacuum The product isthen crystallized from a solvent, alter- 'nately, the product may bechromatographed on alumina and the6fiacetoxy-l7a,20,20,21-bis(methylenedioxy)-16a-methyl-11-oxo-3'-phenyl-5a pregnano [3,2-d] -3H- 1,2,3-triazoleisolated by crystallization of the appropriate eluate.

A solution of 500 mg. of the above product in 35 ml. of tetrahydrofuranwhich has been freshly distilled from lithium aluminum hydride, and asolution of 750 mg. of sodium borohydride in 4 ml. of water are purged 6times with nitrogen and then the solutions are combined. After stirringat room temperature under nitrogen for 18 hours, the combined solutionis cooled to 05 C., and a saturated solution of 4.7 grams of monobasicsodium phosphate is added over a time period of approximately 15minutes. The reaction mixture is stirred for an additional 15 minutes.The slurry is then concentrated under vacuum keeping the temperaturebelow 25 C. until the tetrahydrofuran is essentially removed. The slurryis cooled, filtered and washed with water until neutral. The product isthe6,8-acetoxy-17u,20,20,21-bis(methylenedioxy)-1lfl-hydroxy-16a-methyl-3'-phenyl5a pregnano-[3,2-d]-3'H-1',2',3'-triazole.

To a solution of 436 mg. of the above product in 2.5 cc. of dry dimethylformamide and 2.0 cc. of dry pyridine cooled to C. is added 1.0 cc. ofmethane sulfonyl chloride. The reaction mixture is allowed to warm toroom temperature at which time a precipitate may appear, and is thenheated at 70-80 C. for 10 minutes. The solution is cooled in ice andpoured into ice water. The aqueous solution is then extracted withchloroform. The chloroform layer is washed with sodium bicarbonatesolution, dried over sodium sulfate and then concentrated under vacuum.The crude solution is adsorbed on acid washed alumina from benzenesolution. The column is washed with benzene and the product is elutedwith ether. The ether eluates are evaporated to an oil whichcrystallizes when triturated with ether. The 6 8-acetoxy-l7a,20,20,21-bis(methylenedioxy) 16a-methyl 3' phenyl-9(11)-pregneno-[3,2-d]-3H-1,2,3' triazole product so obtained, is ofsufiicient purity for the next step.

A suspension containing 310 mg. of the above product and 202 mg. ofN-bromosuccinimide in 3.4 cc. of acetone is cooled to 0 C. To thesuspension is added 0.72 ml. of aqueous perchloric acid (0.458 g. of 70%perchloric acid and 16.5 ml. of water). The reaction mixture which isheld at ice temperature becomes homogeneous after 'about 20 minutes andafter about 2 /2 hours is quenched by the addition of 0.12 cc. of allylalcohol. About 20 ml. of water is then added and crystallization isallowed to proceed for /2 hour at 0 C. The crystals are separated byfiltration and dried under vacuum at a temperature that does not exceed25 C. The 6fi-acetoxy-l7u,20,20,2lbis (methylenedioxy) 9a-bromo-11B-hydroxy-16a-methyl-3'-phenyl-5u-pregnano-[3,2-d]-3'H-1,2',3' triazoleso obtained is of sufficient purity for use in the next step.

A suspension of 250 mg. of the above product and 175 mg. of anhydrouspotassium acetate in 5 ml. of absolute ethanol is refluxed for 40minutes under nitrogen. The reaction mixture is cooled, diluted withwater and extracted with chloroform. The chloroform layer is dried oversodium sulfate and then concentrated under vacuum. The crude product isadsorbed on g. of acid washed alumina from a benzene solution. Thecolumn is washed with benzene and eluted with a solvent, the compositionof which depends on the activity of the alumina employed. The eluatesare evaporated to an oil, and crystallized by trituration with ether toafford the 6fl-acetoxy-17u,20,20, 21-bis(methylenedioxy)-9a,11B epoxy16oz methyl-3- phenyl-5a-pregnano-[3,2-d]-3H-1,2',3'-triazole.

A solution of 172 mg. of the above product dissolved in 5 cc. ofchloroform and cooled to 40 C. is added to a reagent consisting of (a)10 cc. of a 2:1 mixture (by weight) of hydrogen fluoride intetrahydrofuran, (b) 10.8 cc. of tetrahydrofuran, and (c) 10 cc. ofchloroform, the reagent being maintained at -80 C. The tetrahydro furanused is of reagent grade and is dried over potassium hydroxide andfiltered. The reaction mixture is placed in a Dewar flask and maintainedat -30 C. for 4 hours. The reaction mixture is then poured into astirred mixture consisting of 25 g. of anhydrous potassium carbonate, 75cc. of a mixture of ice and water, and 70 cc. of chloroform. Thechloroform layer is separated and the aqueous layer is extracted twicewith 2 portions of chloroform. The combined chloroform layers are washedwith water, dried over sodium sulfate, and concentrated under vacuum.The crude product crystallizes from an ether solution on seeding, and isrecrystallized several times from ethyl acetate. The mother liquors arecombined, concentrated and chromatographed on acid washed alumina frombenzene solution. The column is washed 17 a,20,20,21 bis(methylenedioxy)90c fluoro 11 fl-hydroxy-16amethyl-3'-phenyl 5a pregnano-[3,2-d]-3H-1',2',3'-triazole.

A solution of 400 mg. of the above product in 4 ml. of

pyridine is added to the complex formed by the addition of 400 mg. ofchromium trioxide to 4 ml. of pyridine. The mixture is swirled untilthoroughly mixed and then allowed to stand at room temperature overnight. The reaction mixture is poured into water, and the aqueousmixture is extracted with ether and then twice with ethyl acetate. Thecombined ether and ethyl acetate extracts are washed with dilute aqueoussulfuric acid at about 0 C., and then with water until neutral. Theorganic solvent layer is then dried, the solvents are evaporatedtherefrom under vacuum, and the residual crystalline material ispurified by crystallization from a mixture of ethyl acetate and ether togive the 6fl-acetoxy-l7a,20,20, 2l-bis(methylenedioxy)-9a-fluoro 16ccmethyl-ll-oxo- 3'-phenyl-5a-pregnano-[3,2-d]-3H-1',2',3'-triazole.

The above product (1.0 g.) dissolved in 50 ml. of methanol is refluxedfor 15 minutes with 1 g. of potassium hydroxide, dissolved in 5 ml. ofwater. The solution is neutralized with acetic acid :and concentrated toa small volume. The product is then taken up in chloroform and thechloroform layer is washed with water, dried and concentrated undervacuum. Chromatography on acid washed alumina affords the17a,20,20,21-bis(methylenedioxy)-9etfluoro 6 3-hydroxy-l6a-methyl-lloxo-3 phenyl 5apregnano-[3,2-d]-3H-1,2,3-triazole.

A solution of thionyl chloride in pyridine is prepared by adding 7.5 cc.of freshly distilled thionyl chloride to 38 cc. of ice-cold anhydrouspyridine. This is added dropwise to a stirred solution of 7.0 g. ofl7a,20,20,21-bis- (methylenedioxy)-9a-fluoro-6,8 hydroxy-16a-methyl-11oxo-3-phenyl-5a-pregnano-[3,2-d]-3'H-1',23 triazole in 45 cc. ofanhydrous pyridine. The rate of addition is controlled such that thereaction mixture is maintained at approximately 40 C. The solution isstirred an additional 30 minutes after the addition of the reagent iscompleted, subsequently cooled in ice and poured into 250 cc. ofice-water. The mixture is extracted with chloroform and the chloroformlayer is washed with aqueous sodium bicarbonate solution, dried oversodium sulfate and concentrated under vacum. The crude product,dissolved in benzene, is chromatographed on silica gel. Elution withether-petroleum ether, and ether-chloroform mixtures affords the17a,20,20,21-bis(methylenedioxy)- 9a-fluoro-16amethyl-11-oxo-3'-phenyl-5-pregneno-[3,2- d]-3H-1',2,3-triazole.

Example 10 The following procedures which relate to the9a-fluorocompounds of Flow Sheet G are particularly described startingwith the 17a,20,20,21-bis(methylenedioxy)-l6amethyl-l1-oxo-3-phenyl 5pregneno-[3,2-d]-3H-l',2', 3'-triazole and are generally applicable toall the 9a-fluoro starting materials defined by Compound 46 of FlowSheet I.

The 17a,20,20,21 bis(methylenedioxy) 9a fluoro- 16a-methyl 11 oxo 3phenyl 5 pregneno-[3,2-d]- 3H-1,2',3-triazole of Example 9 (1.0 g.) in20 ml. of methylene chloride is added to a stirred mixture consisting of2.6 grams anhydrous hydrogen fluoride, 2.0 grams of lead tetraacetateand 10 m1. of methylene chloride at C. The reaction mixture ismaintained at this temperautre for about 30 minutes and poured into aniced A solution consisting of 500 mg. of the above product and 350 mg.of phenyl iodosodichloride in 20 ml. of anhydrous chloroform is allowedto stand for 3 hours at room temperature. The solution is washed withwater and aqueous sodium bicarbonate solution, dried and concentratedunder vacuum. Chromatography on acid washed alumina afford the17u,20,20,21-bis(methylencdi-

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF 3''-LOWER ALKYL-,PHENYL- AND PARAFLUOROPHENYL14-PREGNENO-(3,2-D)-3''H-1'',2'',3''-TRIAZOLES.